Long-term potentiation (LTP) is a long-lasting form of synaptic plasticity that contributes to some types of learning and memory. For review, see, e.g., Bliss & Collingridge (1993) Nature 361: 31–39. In the hippocampus CA1 region, induction of LTP is dependent on Ca2+ entry into the postsynaptic neuron triggered by N-methyl-D-aspartate receptor activation. See, e.g., Tsien et al. (1996) Cell 87: 1327–1338. The N-methyl-D-aspartate receptor has drawn particular interest since it appears to be involved in a broad spectrum of Central Nervous System disorders. See, e.g., Foster et al. (1987) Nature 329: 395–396; and Mayer et al. (1990) Trends in Pharmacol. Sci. 11: 254–260.
Nitric oxide is a diffusible molecule that can act as a novel type of intercellular messenger in the brain and may act as a retrograde messenger during LTP. See, for example, Son et al. (1996) Cell 87: 1015–1023; and Wilson et al. (1997) Nature 386: 338. Inhibitors of nitric oxide synthase, the enzyme for nitric oxide production, can prevent induction of LTP. One of the downstream effectors of nitric oxide is cGMP, which is also involved in the induction of LTP. cGMP is generated by a soluble guanylyl cyclase. Inhibitors of the soluble guanylyl cyclase suppress LTP. See, for example, Zhuo et al. (1994) Nature 368: 635–639; and Boulton et al. (1995) Neuroscience 69: 699–703. In addition, cGMP controls activities of many proteins, including cGMP-dependent protein kinase G, which may play a role in the induction of LTP. Inhibitors of protein kinase G block induction of LTP, and activators of protein kinase G facilitate the LTP induction in response to weak tetanic stimuli. See, for example, Zhuo et al. (1994) Nature 368: 635–639. Zhuo et al. (1994) Nature 368:, 635–639. Accordingly, a signaling pathway including nitric oxide, cGMP, and protein kinase G is involved in induction of LTP. Identification of compounds that modulate the signaling pathway could provide new therapeutics useful in enhancing learning and memory.